Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive impairment of behavior, language and motor functions caused by neurodegeneration within temporal and frontal brain networks. It is the most frequent cause of dementia under the age of 60. Project 4 of this PPG focuses on differential diagnosis of FTD, which, until recently, was thought to be undistinguishable form Alzheimer's disease (AD) during life. In the previous cycle we have concentrated on identifying distinctive features between FTD and AD and have incorporated our findings into novel research criteria for the behavioral variant (bvFTD), the language variants (primary progressive aphasia-PPA) and the mixed cognitive/behavioral and motor presentation (corticobasal syndromes or CBS) of the disease. The first aim of this application will focus on establishing sensitivity and specificity of these novel classification systems, combined with established PSP-S and amytrophic lateral sclerosis criteria, in predicting in vivo FTLD versus AD pathology. For this purpose we will consider pathology as the gold standard and we will have a large cohort of pathology-confirmed cases that have undergone our extensive clinical and cognitive evaluations. Project 4, and this PPG in general, have also contributed to the recent, discovery that FTD is associated with not only tau aggregates, but also with TDP-43 and FUS. Recognition that the clinical FTD syndrome is associated with a spectrum of diseases at the pathological level (called frontotemporal lobar degeneration-FTLD) poses a new challenge for differential diagnosis that will be tackled by this new project. The second and third aims of Project 4 apply all of the data acquired from the Cores, and some projects, into a multidimensional dataset comprised of clinical, neuroimaging and genetic data that will be analyzed with modern multivariate statistical methods in order to predict in vivo which pathological subtype patients will have, tau, TDP or FUS. By the year 2017 we predict we will have pathological and clinical data on about 250 FTLD cases, creating the largest FTD cohort in the world and allowing us to be at the forefront of diagnosing, and eventually treating, this devastating disease.